Patients with nonvalvular atrial fibrillation at low risk of stroke during
treatment with aspirin

Stroke Prevention in Atrial Fibrillation III study

Authors

The SPAF III writing committee for the Stroke Prevention
in Atrial Fibrillation investigators.

Source

JAMA. 279:1273-7. April 22/29, 1998.

Institutions

Multi-institutional in the U.S. and Canada.

Support

National Institute of Neurologic Disorders and Stroke, Bethesda,
Maryland.

Background

Atrial fibrillation is a common condition, which carries with it a significant
risk for stroke. Treatment with adjusted-dose warfarin significantly reduces
this risk, but at the price of an increased risk for hemorrhage. Treatment
with aspirin also reduces the risk for stroke, but less effectively than
warfarin.

Atrial fibrillation patients are a heterogeneous group with varying
degrees of risk for CVA. Treatment with aspirin could be an attractive
modality for those at low risk for CVA. A number of risk factors for stroke
in atrial fibrillation have been identified. This study, a subgroup of
the SPAF study, was designed to evaluate the stroke risk in a group of
patients without several risk factors, who were prospectively treated
with aspirin only.

Methods

Patients

Patients were eligible if they satisfied all of the following criteria:

Active hypertension (BP greater than 160/90 on two separate days). A history
of hypertension was not an excluding risk factor.

Prior stroke, transient ischemic attack or arterial embolism.

Women older than 75 years of age.

Intervention

All patients who were eligible and participated in the study received
enteric-coated aspirin, 325 mg daily.

Patients were recruited at outpatient clinics in the United States and
Canada. They were followed up by clinic visits every six months and a telephone
contact between clinic visits. At clinic visits blood pressure was determined.
Patients were withdrawn from the study if any of the four risk factors
developed (congestive heart failure, hypertension, emboli/CVA/TIA or women
reaching age 76). Patients withdrawn from the study continued to be followed
up for events; their further treatment (in particular warfarin therapy)
was up to their personal physicians.

Analysis

The primary endpoint was the rate of ischemic strokes and systemic embolism.
Other pre-specified endpoints were disabling ischemic strokes (modified
Rankin score of II or greater at 1 to 3 months) and a stratification of
outcomes according to the presence or absence of a history of hypertension.

A number of other outcomes were also reported, including TIA's, cerebral
and other hemorrhage, vascular events.

The hypothesis was that these patients would have a primary event rate
under 3% per year, and the sample size was determined accordingly.

Results

Patients

892 patients were enrolled between 1993 and 1996. Mean follow-up time
was 2.0 years. Withdrawals from active treatment occurred at a rate of
about 10% per year; 6.5% because of the development of risk factors for
embolism and 3.9% for "other" reasons.

Some patient characteristics included:

Male sex: 78%; mean age: 67 years.

Mean BP: 130/70; history of hypertension: 46%.

Onset of AF less than one year: 77%; paroxysmal AF: 28%.

History of CHF: 9%; history of MI: 7%; diabetes: 13%.

Mean left atrial diameter: 4.6 cms; patients with LA > 5.0 cms: 25%.

Event rates

The primary event rate (ischemic stroke and systemic emboli) was 2.2%
per year (95% CI 1.6-3.0%).

The rate of ischemic stroke was 2.0%, disabling stroke 0.8% and TIA
(not a primary event) 1.3%. The annualized rate of intracranial hemorrhage
was 0.1% and of major, non-CNS hemorrhage 0.6%.

Among the 54% of patients without any history of hypertension, the annual
event rates were substantially lower than among those with such a history:
the primary event rate was 1.1% per year vs. 3.6%, and the rate of disabling
strokes was 0.5% vs. 1.4%.

In multivariate analysis, only a history of hypertension and age were
significant predictors of a primary event.

Author's discussion

The authors suggest that, based on the results of this study, the risk
of stroke in patients without valvular heart disease can be classified
as low, moderate or high.

The risk is low in patients similar to those enrolled in this
trial (without any of the four risk factors) who, in addition, have
no history of hypertension. In this group, the stroke rate is around
1% per year if these patients are treated with aspirin alone, which is
similar to the stroke rate in the general age-matched population. Treatment
with warfarin may not add any significant benefit.

In patients without any of the four risk factors, but with a history
of hypertension are at moderate risk (around 3.5% per year), and
therapy should take into account the risk of anticoagulation and patient
preferences.

Finally, in patients with any of the four risk factors, data from other
branches of the SPAF trials indicate that the event rate is much higher,
around 8% per year even when treated with aspirin and low-dose warfarin.
These patients should be considered for adjusted-dose warfarin therapy
unless there are contra-indications.

The authors note that this trial did not directly compare aspirin with
either placebo or warfarin. Thus, the degree of benefit conferred by aspirin
treatment cannot be inferred from the data presented here. The added protection
that might be gained by using warfarin in these patients can also not be
directly deduced, although the authors use comparisons to other studies
to suggest that it would be relatively low, and at a price of an increased
risk of hemorrhage.

Comment

Patients with "lone atrial fibrillation", who are under 60 years of age,
not hypertensive, without evidence of cardiovascular disease and who have
normal echocardiograms, are at sufficiently low risk for stroke that warfarin
therapy is unlikely to be of significant benefit. Patients who do not fall
into this category (the vast majority) have been shown to benefit from
anticoagulation. However, this large group is not homogeneous. Within it,
some patients are at much higher risk than others. It would make sense
that some of these patients are at sufficiently low risk that they could
be treated with aspirin, or not at all.

Previous trials have identified a number of risk factors for stroke
in the setting of atrial fibrillation. This study made use of this fact
to define a subgroup of patients who did not have lone atrial fibrillation
but were nevertheless felt to be at relatively low risk. These patients
were then treated with aspirin alone and followed up.

Patients who did not have valvular disease, were not actively hypertensive,
did not have left ventricular dysfunction, did not have a history of embolic
phenomena or TIA's and were not women over the age of 75 were enrolled.
Their stroke risk on aspirin alone was 2.2%. More importantly, if patients
with even a past history of hypertension were excluded, the stroke
rate was as low as 1%. It would seem reasonable to withhold coumadin and
treat with aspirin in this subgroup. In the subgroup with a history
of hypertension but without any of the other risk factors, the stroke rate
was about 3.5%. These patients would almost certainly benefit from warfarin
therapy, although not as much as those with one or more of the above mentioned
risk factors.

This study should not be interpreted as showing that warfarin therapy
in atrial fibrillation isn't as important as it would seem to be. The recent
trend in therapy for atrial fibrillation has been to be much more liberal
with anticoagulation, and the current study does not invalidate this trend.
What it does do, however, is define a very specific subgroup of patients
who can probably be managed with aspirin alone. This subgroup represents
a minority of patients, but a significant one.

To be eligible for this strategy, patients must not have mitral stenosis,
any history of hypertension, congestive heart failure (clinically or by
echocardiography), any history of CVA, TIA or embolism and they should
not be women over 75 years of age.

Since this trial did not compare aspirin therapy to warfarin, it is
very possible that warfarin therapy would reduce the stroke rate in this
population even further. Given the low incidence of stroke on aspirin however,
and the not insignificant risk of hemorrhage with warfarin, the overall
benefit is not likely to be large.

The important information gleaned from this trial points out one of
the problems with randomized controlled clinical trials: the populations
which are shown to benefit from a particular intervention are often heterogeneous,
and the benefit may not extend to all subgroups. Prospective analysis of
therapeutic interventions in subgroups is one way to deal with this problem,
and can enable us to target our interventions more appropriately. The RCT
is not the final answer to every possible question.

In this study, the rate of withdrawal that occurred
because of the development of risk factors for embolism was significant
at 6.5% and actually exceeded the rate of any of the primary endpoints.
It is reasonable to speculate that had those patients who developed such
riskfactors remained in the study, the overall stroke
rate in the study patients would have increased. This speculation does
not threaten the study's results but does suggest that we should be cautious
in applying its conclusions to similar patients in our own practices. In
particular, in "real world", non-study, patients, there may be less intensive
follow up and monitoring. It would then become more likely that the development
of risk factors for stroke would be overlooked and treatment with aspirin
continued inappropriately. Phrased differently, the prescription of aspirin
for some patients with atrial fibrillation must not lull usinto therapeutic complacency.

Don't you think aspirin is only antithrombotic
whereas we need anticoagulants to prevent "clotting"? Though it is cheap
and "good", I feel ACs, if monitored properly with PT/INR, should be better
in "lone" (really lone) AFs.

LN

Anticoagulants are probably always better
than aspirin for the prevention of thromboembolism in atrial fibrillation.
The problem with AC's is the risk of bleeding, so that if the absolute
risk of thromboembolism is sufficiently low, the risk of bleeding begins
to outweigh the risk of embolism. Obviously, the risk of bleeding depends
on how stable the INR is, which will depend on multiple factors, including
patient compliance.Again, this study does not demonstrate that
treatment with warfarin should be withheld from any of the patients studied
here, only that it is probably safe to do so in the lowest risk subgroup.
For patients who are very compliant, it remains reasonable to treat with
adjusted dose warfarin. Patient preferences should also be taken into account
in this situation.For patients with truly lone atrial fibrillation
(not studied here) the risk of embolism is even lower, and the benefit
of anticoagulation is thus likely to be even smaller. -- mj